| Eligibility |
Inclusion Criteria:
- 1. Male or female between 18 and 45 years of age, inclusive, at time of informed
consent.
1. Female subjects of childbearing potential must be non-lactating, not pregnant as
confirmed by a negative urine pregnancy test at Screening and admission to
Clinical Research Unit, and using, and agree to continue using, an effective
method of contraception for at least 4 weeks or barrier method for 2 weeks prior
to first study drug administration until 30 days after the last dose of study
drug.
2. Female subjects of non-childbearing potential must be surgically sterile (e.g.,
hysterectomy, bilateral tubal ligation, oophorectomy) or post-menopausal (no
menses for >1 year with follicle stimulating hormone >40 U/L at Screening).
3. Female subjects of childbearing potential must not donate ova during the study
and for at least 30 days after the last dose of study drug.
4. Male subjects who have not had a vasectomy and/or subjects who have had a
vasectomy but have not had 2 post surgery negative tests for sperm must agree to
use an acceptable method of contraception from time of first dose of study drug
until 30 days after the last dose of the study drug, and to not donate sperm
during the study and for at least 30 days after the last dose of study drug.
2. Healthy per investigator judgment as documented by medical history, physical
examination, vital sign assessments, 12-lead ECG, clinical laboratory
assessments, and general observations.
1. At Screening, abnormalities or deviations outside the normal ranges for any
clinical assessments that are considered clinically significant by the
Investigator (laboratory tests, ECG, vital signs) may be repeated once at the
discretion of the Investigator(s), and results that continue to be outside the
normal ranges must be judged by the investigator to be not clinically significant
and acceptable for study participation.
2. On admission to Clinical Research Unit, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), total bilirubin, must be within the upper limits of the
normal range. Subjects with isolated elevation of bilirubin and presumptive
Gilbert's syndrome are permissible. All other laboratory test results that are
outside the reference range on admission to CRU and judged by the investigator to
be not clinically significant may optionally be repeated. Results that continue
to be outside the reference range must be judged by the investigator to be not
clinically significant and acceptable for study participation.
3. Subject must demonstrate clinical euthyroidism as assessed by a thyroid profile
utilizing TSH and Free T4 testing at screening.
3. Body mass index =35.0 kg/m2. 4. Understands the procedures and requirements of
the study and provides written informed consent and authorization for protected
health information disclosure.
5. Willing and able to comply with the requirements of the study protocol.
Exclusion Criteria:
1. Current or past clinically significant history of cardiovascular, cerebrovascular,
pulmonary, gastrointestinal, hematologic, renal, hepatic, immunologic, metabolic,
urologic, neurologic, dermatologic, psychiatric, or other major disease, as determined
by the investigator, which may impact safety. History of cancer (except treated
non-melanoma skin cancer) or history of chemotherapy use within 5 years prior to
Screening.
2. Any surgical or medical condition or history that, in the opinion of the investigator,
may potentially alter the absorption, metabolism, or excretion of study treatment,
such as, but not limited to, gastric bypass surgery or significant small bowel
resections.
3. Contraindication to study drug or its excipients and/or history of allergic or
anaphylactic reactions.
4. Resting heart rate <45 or >110 bpm; blood pressure < 90 or >160 mm Hg systolic, or <50
or >110 diastolic.
5. Waist circumference =38.0 inches for men and =33.0 inches for women.
6. On screening ECG and by history:
1. A marked baseline prolongation of QT/QTcF interval (e.g., repeated demonstration
of a QTcF interval > 450 msec for males and >470 msec for females).
2. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart
failure, hypokalemia, family history of Long QT Syndrome) or a family history of
sudden cardiac death of unknown origin.
7. Taking any of the following prohibited medications:
a. Limited background prescription medications are permitted to manage complications
of obesity, but any drug known to inhibit or induce cytochrome P450 (CYP) enzymes
and/or P-glycoprotein including St. John's wort (Hypericum perforatum) within 14 days
or 5 half-lives (whichever is longer) prior to admission to CRU, is prohibited. Also
prohibited is the use of concomitant medications that prolong the QT/QTc interval
identified in the https://crediblemeds.org/ website list category of 'Known Risk'.
Over the counter multi-vitamin supplements, including products with CBD, or any
non-prescription products (including herbal-containing preparations) are prohibited
within 14 days prior to admission to CRU or during the conduct of the trial.
Acetaminophen may be taken during screening, but should not receive a dose within 24
hours of admission to the CRU.
i) Exception: hormonal contraceptives and hormone replacement therapies (oral,
injectable, transdermal or implanted) are permitted.
8. History of significant drug abuse within one year prior to Screening or frequent use
of soft drugs (such as marijuana) within 3 months prior to the Screening visit, or
hard drugs (such as cocaine, phencyclidine [PCP], opioid derivatives including heroin,
and amphetamine derivatives) within 1 year prior to screening.
9. History of regular alcohol consumption exceeding 14 drinks/week [1 drink = 5 ounces
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor]
within 6 months of Screening.
10. Positive urine drug or urine alcohol test at Screening or on admission to CRU.
11. Current nicotine use or vaping regularly more than 5 cigarettes or the equivalent per
week. Use of nicotine patches for smoking cessation is not permitted within 7 days of
dosing.
12. Consumed any food or drink/beverage containing grapefruit or grapefruit juice, apple
or orange juice, pomelo juice, star fruit, Seville or Moro (blood) orange products
within 6 days before admission to CRU. Vegetables from the mustard green family (e.g.,
kale, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, mustard), food
containing poppy seeds (e.g., muffins, bagels, and cakes) must not be consumed within
24 hours before admission to CRU.
13. Positive test results of hepatitis B surface antigen (HBsAg), hepatitis C virus
antibody (HCV Ab), or human immunodeficiency virus (HIV1/2) antibody.
14. Diabetes reflected by a fasting plasma glucose level of =126 mg/dL and a reflex HbA1c
of =6.5%.
15. Neutropenia, defined as absolute neutrophil count =1000/microL.
16. Participation in another clinical trial at the time of screening or exposure to any
investigational agent, including topical, within 30 days or 5 half-lives prior to
admission to CRU, whichever is longer.
17. Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding
volume drawn at screening) of 50 mL to 499 mL of blood within 30 days, or more than
499 mL within 56 days prior to the first dosing.
18. Received a tattoo or body piercing (including ear piercings) within 2 months prior to
Day 1, and/or significant open wound that may result in risk of infection.
19. Having a condition that the investigator believes would interfere with his/her ability
to provide written informed consent, comply with study instructions, or which might
confound the interpretation of the study results or put the subject at undue risk.
Subjects with a history of hypo- or hyperthyroidism, peripheral neuropathy, malignant
hyperthermia, cataracts or chronic recurrent rash that is considered clinically
significant by the investigator are excluded.
20. Must not be claustrophobic or have a history of claustrophobia, or intolerance of
closed or small spaces.
21. Familial (mother/father/sibling) and/or personal history of retinal detachment any
time in the past.
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